The present invention relates generally to carbocyclic imidodisulfamides, as well as their alkali salts and N-monophosphates. The compounds of this invention possess broad antiviral activity, especially activity against orthopox viruses.
Ali at al., J. Med. Chem. 25: 1235-1240 (1982) describe a series of N,N1-bis(arylcyclopropyl)imidodisulfamide derivatives having antiallergic activity. Appel and Helwerth, Chem. Ber. 101: 1743-1745 (1968) disclose a bis(cyclohexyl)imidodisulfamide derivative. Yamaguchi and Nakano [Japan. Patent 19,962 (1963)] disclose the ammonium salt of a bis(cyclohexyl)imidodisulfamide derivative.
In accordance with the invention, there are provided carbocyclic imidodisulfamide compounds of the formula:
[Rxe2x80x94(CR2R3)nNHSO2]2NR1xe2x80x83xe2x80x83(I)
or pharmaceutically acceptable salts or solvates of said compound, wherein: n is a number from 0 to 6, R is a carbocyclic radical selected from the group consisting of adamantyl, norbornyl, cyclooctyl and cyclododecyl, R1 is selected from the group consisting of hydrogen, alkali metal, ammonium cation, and monophosphate moiety, and R2 and R3 can be the same or different and are independently selected from the group consisting of H and lower alkyl, further wherein said carbocyclic radical can be optionally substituted with one or more substituents selected from the group consisting of lower alkyl, F, Cl, Br, NO2 and CF3.
The invention further provides a method for treating a warm blooded animal for viral infections, preferably but not limited to infections caused by orthopox viruses (such as vaccinia virus, cowpox, smallpox, monkeypox, camelpox, etc.) which method comprises administering to such animal an therapeutically effective amount of at least one compound of formula (I).
This invention additionally provides a pharmaceutical composition comprising at least one compound of formula I and at least one pharmaceutically acceptable carrier.
In an embodiment, this invention provides imidodisulfonamide compounds of formula I, wherein R, n, R1, R2 and R3 are described above.
[Rxe2x80x94(CR2R3)nNHSO2]2NR1xe2x80x83xe2x80x83(I)
Except where stated otherwise, the following definitions apply throughout the present specification and claims. These definitions apply regardless of whether a term is used by itself or in combination with other terms. Hence the definition of xe2x80x9calkylxe2x80x9d applies to xe2x80x9calkylxe2x80x9d as well as to the xe2x80x9calkylxe2x80x9d portions of xe2x80x9calkoxyxe2x80x9d, xe2x80x9calkylaminoxe2x80x9d etc.
As used above, and throughout the specification, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
xe2x80x9cPatientxe2x80x9d includes both human and other animals.
xe2x80x9cMammalxe2x80x9d means humans and other mammalian animals.
xe2x80x9cAlkylxe2x80x9d means an aliphatic hydrocarbon group, which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. xe2x80x9cLower alkylxe2x80x9d means an alkyl group having about 1 to about 6 carbon atoms in the chain, which may be straight or branched. The term xe2x80x9csubstituted alkylxe2x80x9d means that the alkyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, -cycloalkyl, cyano, hydroxy, alkoxy, and xe2x80x94C(O)O-alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, and t-butyl.
xe2x80x9cAlkenylxe2x80x9d means an aliphatic hydrocarbon group comprising at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. xe2x80x9cLower alkenylxe2x80x9d means an alkenyl group having about 2 to about 6 carbon atoms in the chain, which may be straight or branched. The term xe2x80x9csubstituted alkenylxe2x80x9d means that the alkenyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, -cycloalkyl, cyano, and alkoxy. Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, and 3-methylbut-2-enyl.
xe2x80x9cArylxe2x80x9d means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be unsubstituted or substituted on the ring with one or more substituents which may be the same or different, each being independently selected from the group consisting of alkyl, aryl, OCOalkyl, OCOaryl, CF3, heteroaryl, aralkyl, alkylaryl, hydroxy, alkoxy, aryloxy, halo, nitro and cyano. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. The xe2x80x9carylxe2x80x9d group can also be substituted by linking two adjacent carbons on its aromatic ring via a combination of one or more carbon atoms and one or more oxygen atoms such as, for example, methylenedioxy, ethylenedioxy, and the like.
xe2x80x9cAralkylxe2x80x9d means an aryl-alkyl-group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.
xe2x80x9cAlkylarylxe2x80x9d means an alkyl-aryl-group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non-limiting example of a suitable alkylaryl groups is tolyl. The bond to the parent moiety is through the aryl.
xe2x80x9cCycloalkylxe2x80x9d means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted on the ring by replacing an available hydrogen on the ring by one or more substituents which may be the same or different, each being independently selected from the group consisting of alkyl, aryl and heteroaryl. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like.
xe2x80x9cHaloxe2x80x9d means fluoro, chloro, bromo or iodo groups. Preferred are fluoro, chloro or bromo, and more preferred are fluoro and chloro.
xe2x80x9cHalogenxe2x80x9d means fluorine, chlorine, bromine or iodine. Preferred are fluorine, chlorine or bromine, and more preferred are fluorine and chlorine.
xe2x80x9cAlkoxyxe2x80x9d means an alkyl-Oxe2x80x94 group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy and isopropoxy. The alkyl group is linked to an adjacent moiety through the ether oxygen.
The term xe2x80x9coptionally substitutedxe2x80x9d means optional substitution with the specified groups, radicals or moieties.
As used herein, the term xe2x80x9ccompositionxe2x80x9d is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term xe2x80x9cprodrugxe2x80x9d, as employed herein, denotes a compound that is a drug precursor, which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of formula I or a salt and/or solvate thereof. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) Volume 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, both of which are incorporated herein by reference thereto.
xe2x80x9cSolvatexe2x80x9d means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. xe2x80x9cSolvatexe2x80x9d encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. xe2x80x9cHydratexe2x80x9d is a solvate wherein the solvent molecule is H2O.
xe2x80x9cEffective amountxe2x80x9d or xe2x80x9ctherapeutically effective amountxe2x80x9d is meant to describe an amount of compound of the present invention effective to treat a mammal (e.g., human) having a disease or condition mediated by orthopox viruses, and thus producing the desired therapeutic effect.
The compound of formula I forms salts which are also within the scope of this invention. Reference to a compound of formula I, herein is understood to include reference to salts thereof, unless otherwise indicated. The term xe2x80x9csalt(s)xe2x80x9d, as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of formula I contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions (xe2x80x9cinner saltsxe2x80x9d) may be formed and are included within the term xe2x80x9csalt(s)xe2x80x9d as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compound of the formula I may be formed, for example, by reacting a compound of formula I with an amount of acid or base, such as, for example, an equivalent amount, in a medium such as, for example, one in which the salt precipitates or in an aqueous medium followed by lyophilization.
Exemplary acid addition salts include acetates, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulforiates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, maleates, sulfonates, tartrates and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food and Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.
Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
Thus, for example, alkali metal salts may be formed by treating the compounds with aqueous alkaline hydroxide solution such as but not limited to sodium hydroxide and potassium hydroxide.
The compounds of this invention may also be utilized in the form of N-substituted monophosphates. Such derivatives may be formed by treating the compounds 1 with phosphorylating agent such as but not limited to phosphoryl oxychloride, phosphorus trichloride.
All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
Compounds of formula I, and salts, solvates and prodrugs thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.
All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates and prodrugs of the compounds as well as the salts and solvates of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms xe2x80x9csaltxe2x80x9d, xe2x80x9csolvatexe2x80x9d xe2x80x9cprodrugxe2x80x9d and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrugs of the inventive compounds.
When any variable (e.g., aryl, heterocycle, R2, etc.) occurs more than one time in any constituent or in formula I, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The compounds of the invention may be prepared by reacting an appropriate carbocyclic alkylamine derivative (1) with imidodisulfuryl chloride (2) in the presence of triethylamine (n, R, R2 and R3 are as defined above): 
The following carbocyclic alkylamine intermediates (1) are commercially available: tricyclo[3.3.1.13,7]decan-1-amine (1; R=1-adamantyl, n=0); [(tricyclo[3.3.1.13,7]-dec-1-yl)methyl]amine (1; R=1-adamantylmethyl, n=1); tricyclo[3.3.1.13,7]decan-2-amine (1;R=2-adamantyl, n=0); exo-bicyclo[2.2.1]heptan-2-amine (1; R=exo-2-norbornyl, n=0); and endo-bicyclo[2.2.1]heptan-2-amine (1; R=endo-2-norbornyl, n=0).
Tricyclo[3.3.1.13,7]decan-1-ethanamine (1; R=1-adamantyl, n=2) may be prepared according to U.S. Pat. No. 3,534,036 of V. L. Narayanan and F. L. Weisenborn, the entire disclosure of which is incorporated herein by reference.
Tricyclo[3.3.1.13,7]decan-2-ethanamide (1; R=2-adamantyl, n=2) and 2-(tricyclo[3.3.1.13,7]dec-2-ylidene)ethanamine (4): 
were prepared according to the procedure of Mariani and Schenone, II Farmaco, Ed. Sci. 31: 272-276 (1976) and Schenone et al. II Farmaco, Ed. Sci. 27: 322-332 (1972).
Imidodisulfuryl chloride was prepared utilizing the procedure of Appel and Eisenhouer, Chem. Ber. 95: 1753 (1962).
The compounds of the invention may also be prepared as their ammonium salts (6) by reacting an appropriate carbocyclic alkylamine derivative (1) (n, R, R2 and R3 are as defined above) with the ammonium salt of imidodisulfuryl chloride (5) according to the procedures of Appel and Helwerth [Chem. Ber. 101: 1743-1745 (1968)] and Yamaguchi and Nakano [Japan. Patent 19,962 (1963)]: 
In order to increase their solubility in water and saline, the compounds of the invention may also be prepared as their alkali salts (8) by reacting an appropriate carbocyclic imidodisulfamide derivative 3 (n, R, R1, R2 and R3 are defined as above) with aqueous alkaline hydroxide solution such as but not limited to sodium hydroxide and potassium hydroxide: 
In order to increase their solubility in water and saline, the compounds of the invention may also be prepared as their N-substituted monophosphate derivatives (10) according to the procedure of Zavlin and Efremov, Phosphorous Sulfur, 40: 247-251 (1991) by reacting an appropriate carbocyclic imidodisulfamide derivative 3 (n, R, R2 and R3 are as defined above) with a phosphorylating agent 9 (e.g., phosphoric anhydride, phosphorus trichloride, phosphorous pentoxide and phosphorous oxychloride): 
By having increased solubility in water and saline, compounds of the formula 6, 8 and 10 may be easily administrated by oral, intranasal, and intraperitoneal routes to treat warm-blooded animals against infections caused by orthopox viruses.
The present invention is illustrated in more detail by reference to the following non-limiting examples.